Generally, the term tumor necrosis factor (TNF) refers to two closely related cytokines (encoded by separate genes) known as tumor necrosis factor-alpha (TNF, cachectin) and tumor necrosis factor-beta (lymphotoxin, TNF-beta). Both cytokines interact with the same cell membrane receptors, and both have been implicated as pathogenic mediators of human illness.
TNF-alpha participates in the signaling pathways that regulate cell apoptosis and inflammation. TNF-alpha is also known as TNFSF2, TNFA and DIF. TNF-alpha is a pro-inflammatory mammalian protein capable of inducing cellular effects by virtue of its interaction with specific cellular receptors. It is produced primarily by activated monocytes and macrophages. Lipopoly-sacccharide (LPS, also called endotoxin), derived from the cell wall of gram negative bacteria, is a potent stimulator of TNF-alpha synthesis.
Due to the deleterious effects which can result from an over-production or an unregulated production of TNF-alpha, considerable efforts have been made to regulate the tissue or serum level of TNF-alpha. The pathology of a number of diseases are affected by TNF-alpha, including, restinosis, inflammatory diseases of the central nervous system, demyelinating diseases of the nervous system, multiple sclerosis, septic arthritis, aneurysmal aortic disease, traumatic joint injury, periodontal disease, macular degeneration, diabetic retinopathy, occular inflammation, keratoconus, Sjogren's syndrome, corneal graft rejection, cachexia, and anorexia.
While a number of inhibitors of TNF-alpha levels and activity have been reported, it is not clear whether they possess the appropriate pharmacological properties to be therapeutically useful. Therefore, there is a continued need for small molecule TNF-alpha inhibitors that are potent, stable, and have good penetration through membranes to provide effective inhibition of apoptosis in vivo. Such compounds would be extremely useful in treating the aforementioned disease states where TNF-alpha cytokines play a role.